tbuckley/cabot-search huggingface dataset:
CNSC-14. T-TYPE CALCIUM CHANNELS REGULATE NEURON-GLIOBLASTOMA INTERACTIONS AND PROMOTE TUMOR GROWTH
Authors: Collin Dube, Ying Zhang, Shekhar Saha, Michelle Lai, Myron Gibert, Miguel Escalante, Kadie Hudson, Ulas Yener, Farina Hanif, Benjamin Kefas, Esther Xu, Aditya Sorot, Harald Sontheimer, Roger Abounader
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with a dismal median survival of 15 months. Glioblastoma utilizes calcium signaling to regulate communication between tumor cells and the neuronal microenvironment. T-type calcium channels (TTCCs) are voltage gated calcium channels expressed in various types of neurons throughout the brain regulating glutamatergic synaptic transmission. We analyzed spatial transcriptomics of human GBM tumors and found that TTCCs are expressed in infiltrating tumor regions and enriched for neuronal development spatial patterns and exhibit neurodevelopmental signatures. Analysis of single cells transcriptomic of human GBM tumors demonstrated that TTCCs are enriched in neuronal subtypes. To complement publicly available data,we treated Glioblastoma Stem cells (GSCs) with an FDA-approved repurposed TTCC blocker, mibefradil, and found downregulation of genes associated with neuron processes such as synapse organization, postsynaptic density and glutamatergic synapses. Treatment of GSCs with mibefradil abrogated cell proliferation in the presence of glutamate. We examined the effects of neuronal Cav3.2 on GBM growth. Genetic Cav3.2 knockout (Cav3.2 KO) in the microenvironment of mice xenografted with syngeneic cell lines (GL261 and CT2A) exhibited significant tumor volume reduction as well as increased survival compared to WT mice in both cell lines. Cav3.2 KO tumors exhibited a decrease in proliferation (Ki67+) and neuronal connections (VGlut1) measured by immunofluorescence compared to WT mice. Cav3.2KO neuron-GBM co-cultures exhibited a significant decrease in proliferation compared to WT neuron-GBM co-cultures. Cav3.2KO neuron-GBM co-cultures exhibited a decrease in synaptic connections and a decrease in neuronal projections to GBM cells compared to WT neuron-GBM co-cultures. Transcriptomic analysis of tumors from Cav3.2KO tumors revealed deregulation of genes associated synaptic transmission, glutamatergic synapses and postsynaptic specialization. Altogether, our findings indicate a role of Cav3.2 in regulating tumors and neurons and promoting GBM progression.
PATH-45. OUTCOMES OF AN IRRADIATION SPARING APPROACH IN MEDULLOBLASTOMA BY SUBGROUP IN YOUNG CHILDREN: AN INSTITUTIONAL REVIEW
Authors: Rebecca Ronsley, Stephen Yip, Christopher Dunham, Juliette Hukin, Jonathan Finlay
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with an irradiation-sparing approach. METHODS Retrospective analysis of clinical outcomes including treatment, relapse and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children’s Hospital (BCCH) between 2000 and 2020. RESULTS There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH, (n=14), Group 3 (n=7), Group 4 (n=6) and indeterminate status (n=3). Three and 5-year event-free survival (EFS) and overall survival (OS) were 49.0% (30.2 and 65.4%) and 42.0% (24.2-58.9%) and 62.5% (42.4 and 77.2%) and 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%) respectively, with a median follow up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (Group 4: n=4, Group 3: n=1, unknown: n=1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow up of seven years. Disease/treatment-related morbidity included endocrinopathies (n=8), hearing loss n=16), and neurocognitive abnormalities (n=9). CONCLUSIONS This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with Group 3 and 4 medulloblastoma, relapse rates were high; however, most Group 4 patients were salvaged with RT.
NCOG-14. EFFECT OF CHOLINE ALPHOSCERATE ON THE SURVIVAL OF GLIOBLASTOMA PATIENTS
Authors: Yeong Jin Kim
Journal: Neuro-Oncology (2023)

Abstract Cognitive impairment often occurs in glioblastoma (GBM) patients due to the tumor itself and treatment side effects. Choline alphoscerate (L-alpha-glycerylphosphorylcholine, GPC) is frequently used to compensate for cognitive impairment in GBM patients. This study was conducted to determine whether GPC affects the overall survival (OS) and progression-free survival (PFS) of GBM patients. From 2011 to 2020, 187 isocitrate dehydrongenase (IDH)-wild-type GBM patients were analyzed. The patients were classified based on whether GPC was continuously used for at least 3 or 12 months (mos) after GBM diagnosis. Although GPC usage (≥3 mos) did not make significant differences in survival extension, median OS in the long-term GPC group (≥12 mos) was longer with statistical significance, compared to the control group (&amp;lt; 12mos)(38.3 vs 24.0 mos, p=0.004). In addition to younger age, supratentorial location, complete resection, and MGMT promoter methylation, long-term use of GPC (≥12 mos) was significantly associated with longer OS in multivariate analysis (p = 0.019, hazard ratio [HR] 0.532, 95% confidence interval [CI] 0.314–0.900). Despite the limitations of this study, long-term GPC use was possibly associated with prolonged survival in GBM patients. Multi-center prospective randomized studies with a large number of patients are needed to validate these findings.
NIMG-15. COMBINED ADVANCED IMAGING AND MGMT STATUS FOR DISTINCTION BETWEEN EARLY TUMOR PROGRESSION AND PSEUDOPROGRESSION IN GLIOBLASTOMA
Authors: Maria Diaz, Adela Joanta-Gomez, Denisse Torres, Julia Furnari, Nahill Matari, Peter Canoll, Angela Lignelli, Andrew Lassman
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Within 3-6 months of completing initial chemoradiotherapy, up to 50% of glioblastomas (GBM) develop worsening contrast enhancement on surveillance imaging, which could represent early progression (EP) or pseudoprogression (PsP). Reports suggest EP is more common in MGMT unmethylated (uMGMT) cases. While multiple advanced imaging studies have tried to address this issue (including magnetic resonance with perfusion [MRP], with spectroscopy [MRS], and FDG-PET), no non-invasive test reliably differentiates EP from PsP, yet the distinction is critical for subsequent management. We aimed to develop a multiparametric score including advanced imaging and MGMT status to improve interpretation. METHODS We retrospectively reviewed records of patients diagnosed with GBM from 2016-2022 who had changes on anatomic imaging concerning for EP vs. PsP ≤6 months after chemoradiotherapy and underwent ≥ 2 advanced imaging sequences (MRP, MRS, FDG-PET); definitive distinction between EP and PsP was made by either histology from surgical resampling or subsequent clinico-radiographic evolution. Associations between clinical factors and EP were investigated with logistic regression. Sensitivity and specificity of each imaging modality and of a composite score (1 point each for MRP consistent with EP, MRS consistent with EP, and uMGMT) were calculated. RESULTS 46 evaluable patients (57% male; median age 58.5 years, range 31-80) were included; outcome (EP in 29 [63%], PsP in 17 [37%]) was determined histologically and clinically in 15 (33%) and 31 (67%) of cases, respectively. In multivariate analysis, uMGMT was predictive of EP (OR=2.63, 95% CI=1.29-37.55, p&amp;lt; 0.05). Sensitivity/specificity to predict EP were 78%/77% for uMGMT, 76%/29% for MRP, 85%/67% for MRS, 86%/0% for FDG-PET (8 patients) and 88%/75% for composite score of 2-3 (vs. 0-1). CONCLUSION Combining MRS, MRP and MGMT results can improve accuracy in distinguishing EP from PsP in GBM. MGMT status should be incorporated in the interpretation of advanced imaging to distinguish EP from PsP.
BIOM-20. <i>NEAT1</i> EXPRESSION IS ASSOCIATED WITH GLIOBLASTOMA PATIENT RESPONSE TO IMMUNE CHECKPOINT INHIBITORS
Authors: Joseph Toker, J Bryan Iorgulescu, Alexander Ling, Genaro Villa, Laxmi Parida, Gad Getz, Catherine Wu, David Reardon, E Antonio Chiocca, Marco Mineo
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Despite advances in therapeutic intervention, including maximal tumor resection, chemotherapy, and radiotherapy, GBM patient median survival remains approximately 20.9 months. A promising approach to overcome current therapeutic challenges is the use of inhibitors of immune checkpoints, such as PD-1/PD-L1, which have been demonstrated to be effective against many different solid cancers. Despite the strong interest in applying these strategies to GBM, clinical studies evaluating the efficacy of monoclonal antibodies against PD-1/PD-L1 have yielded disappointing results. However, an analysis of the data from these studies, considering clinical factors such as MGMT promoter methylation and the use of steroids, indicated that immune checkpoint inhibitor (ICI) therapy may benefit a subset of GBM patients. Moreover, additional clinical studies in GBM have demonstrated the importance of the timing of ICI treatment, although the markers associated with response remain unclear. Therefore, understanding the molecular basis of clinical response to PD-1/PD-L1 inhibitors is critical to identify GBM patients who can benefit from this type of therapy. By analyzing the transcriptomic profile of two different cohorts of GBM patients, we identify NEAT1 as a long noncoding RNA upregulated in GBM patients with longer survival upon anti-PD-1/PD-L1 treatment. Higher expression of NEAT1 was associated with upregulation of the interferon-gamma pathway and downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analysis showed that higher NEAT1 expression in tumor cells correlated with the number of infiltrating macrophages and microglia. Among the GBM immune infiltrates, we found that macrophages and microglia had the highest NEAT1 median expression. Macrophage expression of NEAT1 was associated with enrichment in the TNF-alpha signaling pathway and the regulation of different inflammatory cytokines. Our findings suggest that NEAT1 is an important factor in shaping the tumor-immune microenvironment and a potential marker to predict GBM patient response to ICI.
RADT-49. A SYSTEMATIC REVIEW AND META-ANALYSIS OF HIPPOCAMPAL AVOIDANCE IN WHOLE BRAIN RADIOTHERAPY AND PROPHYLACTIC CRANIAL IRRADIATION
Authors: Sandra Leskinen, Harshal Shah, Beril Yaffe, Shonna Schneider, Netanel Ben-Shalom, John Boockvar, Randy D'Amico, A Gabriella Wernicke
Journal: Neuro-Oncology (2023)

Abstract PURPOSE: Hippocampal-avoidance radiotherapy has been under investigation as a technique to improve neurocognitive function in patients undergoing whole brain radiotherapy (WBRT) for intracerebral tumor treatment and control. To understand the effectiveness of hippocampal-avoidance radiotherapy compared to conventional radiotherapy, we systematically reviewed hippocampal-avoidance WBRT (HAWBRT) and hippocampal-avoidance prophylactic cranial irradiation (HAPCI). METHODS: We searched the PubMed database for studies involving hippocampal-avoidance radiation therapy, adhering to PRISMA guidelines. Included studies were analyzed for median overall survival, progression-free survival, hippocampal relapse rates, and neurocognitive function testing. RESULTS: Our initial search identified 3709 results, of which 22 studies were ultimately included and a total of 1749 patients analyzed. Seven of the included studies were randomized controlled trials, five were prospective cohort studies, and ten were retrospective cohort studies. Brain metastases were the most commonly treated tumor. There were 19 studies (86.4%) that evaluated HAWBRT and/or HAPCI in patients with brain metastases. Rates of hippocampal relapse were low (overall effect size = 0.04; 95% confidence interval [0.03, 0.05]) and there was no significant difference in risk of relapse between HAWBRT and conventional WBRT (n=5 studies; risk difference = 0.01; 95% confidence interval [-0.02, 0.03]; p = 0.63). Among the thirteen studies that assessed changes in neurocognitive function, significant differences were identified in overall cognitive function and memory/verbal learning 3-24 months post-RT. Significant differences in processing speed and executive function were reported by some studies at 4 and 6 months. No studies reported differences in verbal fluency, visual learning, concentration, and psychomotor speed at any timepoint. CONCLUSION: Analyzed studies in HA-WBRT/HA-PCI showed low hippocampal relapse or metastasis rates. Significant differences in neurocognitive testing were most prominent in overall cognitive function, memory, and verbal learning. Studies were often hampered by loss to follow-up. Further studies into the effectiveness of HA-WBRT are warranted.
QLTI-10. STANDARD WORK FOR ORAL CHEMOTHERAPY IMPROVES SAFETY WITHOUT INCREASING DELAYS
Authors: Samantha Balakrishnan, Seema Nagpal, Anisia Dugala, Gwen Coffey, Justine Pena
Journal: Neuro-Oncology (2023)

Abstract Purpose Oral chemotherapy in the outpatient setting does not have the same level of oversight as chemotherapies delivered in an infusion treatment area. This project aimed to create a standardized process to prescribe outpatient oral chemotherapy to improve patient safety. The primary process-measure was laboratory data review prior to ordering therapy, with primary outcome-measure being number of days between approval to administer therapy and actual administration. A secondary process-measure was documentation quality, and counterbalance-measure was delay in ordering due to lab review. METHODS A Failure Mode Effects Analysis was performed. Standard work was developed for each step of prescribing and roles and responsibilities were assigned for each step in the process. A checklist was developed within the medical record to review and document essential steps in the process allowing for greater visibility. Fifty-three patient encounters were reviewed prior to intervention and 39 post-intervention. RESULTS FMEA identified 7 high-risk points. For the primary process measure, prior to intervention, 34/53 (64%) encounters had laboratory data review prior to chemotherapy order. After intervention, 38/39 (97%). The change did not delay ordering; we observed a mean 2-day delay between laboratory data review and chemotherapy order (significant difference from zero [p = 0.001]) pre-intervention. After intervention, there was no statistically significant delay (mean -0.74 days, p = 0.376). Documentation improved after intervention; 23/53 (43%) chemotherapy encounters contained complete data pre-intervention, and 36/39 encounters (92%) post-intervention. CONCLUSIONS As part of our standardized process, we developed a new chemotherapy checklist and flowsheet in the medical record. While the fraction of patients with zero delay in chemotherapy administration after approval did not change, patient safety improved with more patients having laboratory review prior to chemotherapy order. This review did not increase delays in ordering therapy. Documentation quality also improved. Having a standard process increases patient safety while prescribing outpatient oral chemotherapy.
CTNI-10. SACITUZUMAB GOVITECAN FOR BREAST CANCER BRAIN METASTASIS
Authors: Henriette Balinda, William Kelly, Pegah Ghamasaee, Andrea Gilbert, Joel Michalek, Virginia Kaklamani, Kate Lathrop, Prathibha Surapaneni, John Floyd, Andrew Brenner
Journal: Neuro-Oncology (2023)

Abstract Breast cancer brain metastasis (BCBM) is a challenge that significantly impacts patient prognosis and quality of life. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and is approved for triple negative and HR+/HER2 negative metastatic breast cancer. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. SG activity was tested in a breast cancer intracranial mouse model. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for breast cancer brain metastases (n = 13). We enrolled patients aged ≥18 years diagnosed with brain metastatic breast cancer to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. SG significantly inhibited tumor growth and increased overall survival in mice. An average of 1953.79 ng/ml in serum and 134.3 ng/g in tissue of SN-38 was quantified in patient samples. Trop-2 expression was observed in 100% of patient tumors. 41% of the samples showed high expression of CAIX. A positive correlation between the tissue:serum [SN-38], Trop-2 and gH2AX staining was observed. Median overall survival of 34.5 months (5.7 - 35.6 months) and progression free survival of 7.4 months (2 – 24.4 months) were observed. Our data suggest that SG has therapeutic potential in patients with breast cancer brain metastasis. A prospective multicenter cooperative trial of SG for BCBM, S2007, is ongoing and an update on accrual will be provided.
SURG-38. SAFETY AND EFFICACY OF COMBINATORIAL IMMUNE CHECKPOINT BLOCKADE AND LASER INTERSTITIAL THERMAL THERAPY
Authors: Aden Haskell-Mendoza, Lucas Wachsmuth, Ethan Srinivasan, Joshua Jackson, Saif Zaidi, Ariel Gonzalez, Elle Reason, Emily Lerner, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Treatment of intracranial lesions with laser interstitial thermal therapy (LITT) allows for simultaneous cytoreduction and the potential to generate an anti-tumor immune response. The safety and efficacy of combination immune checkpoint blockade (ICB) and LITT has not been determined. METHODS All patients who received LITT for neuro-oncologic indications at a single NCI-designated cancer center from 2015 – 2022 were included. Simultaneous ICB was defined as receipt of therapy within 6 weeks of LITT. Demographic, clinical, and survival data were collected. Immune-related and intracranial adverse events (iRAEs and IAEs) were graded according to Common Terminology Criteria. RESULTS Twenty-four patients received simultaneous LITT and ICB. Median age was 62 (range 40 - 78) and 12 (48%) were female. Median KPS was 80 (50 – 100). Use of ICB increased during the study period (r = 0.69). The most common pathology was non-small cell lung cancer (15 patients, 62.5%), followed by melanoma in 3 (12.5%) and 2 (8.3%) patients each with renal cell carcinoma or high-grade glioma. Twenty-three (96%) patients received single agent ICB, with pembrolizumab most common (12, 50%), followed by nivolumab (6, 25%). The median interval between LITT and ICB was 2.56 (0.85 – 4.98) weeks. The most common iRAE was hypothyroidism in 4 (16.6%) patients, with grade 3 pneumonitis in one patient. The most common IAE was seizures in 4 (16.6%) patients. Local progression was seen in 4 patients (16.6%), with a post-LITT overall survival of 20.6 (1.0 – 36.1) months for the cohort. CONCLUSIONS Combination LITT and ICB appears safe and effective, with iRAEs commensurate with trials of checkpoint inhibition. High-grade intracranial toxicity was rare. Prospective studies of combinatorial LITT + ICB are needed to establish biomarkers and optimal timing.
INNV-28. SCIENTIFIC LITERACY AND DECISION-MAKING OF PATIENT FAMILIES IN PEDIATRIC NEURO-ONCOLOGY
Authors: Nicole Lyons, Lisa Ward
Journal: Neuro-Oncology (2023)

Abstract Pediatric neuro-oncology, especially when treating typically terminal tumors such as DIPG, exists in a fluid, complicated state. There exists no standard, effective, and tolerable treatment. This means all patients are on clinical trials for treatment, placing the child’s care on the cutting edge of an already complicated field of research. A concern frequently brought up by parents is the struggle to understand scientific articles about their child's condition. Without a solid foundational understanding of molecular biology, the majority of their time reading research is spent googling terms only scientists are familiar with. A survey of 40 questions was developed and disseminated amongst families of children diagnosed with DIPG/DMG via email, with 64 participants The intent was to investigate what level of relevant scientific literacy the average parent had at diagnosis, during decisions on treatment, and where it is currently. RESULTS: showed at the time of diagnosis, 89.4% of families had never heard of Diffuse Intrinsic Pontine Glioma, let alone understood its mechanisms and treatment options. There is existing patient education, but current education does not go into the level of scientific detail needed. The result shows that 86.5% of families are spending at least 10 hours each week researching conditions outside of doctor appointments. At the time of diagnosis, 84.4% of families have little to no familiarity with clinical trials at all, yet 61.4% of those families are making decisions on participation under a month from diagnosis. The decisions families make impact patients’ quality of life, the development of effective and safe treatments, and if their child passes, their grieving. A better understanding of disease and treatment has been consistently shown to result in better outcomes by a variety of measures. Patient education focused on scientific literacy is desperately needed to match families' decision-making needs.